Substituted 3 3-diphenylpiperazines and 3 3-diphenylpiperazin-2-ones

ABSTRACT

THE DISCLOSURE IS DIRECTED TO SUBSSTITSUTED 3,3-DIPHENYLPIPERAZINES, SUBSTITUTED 3,3-DIPHENYLIPERAZIN-2-ONES AND RELATES COMPOUNDS. THE COMPOUNDS ARE USEFUL AS SYMPATHOMIMETIC AGENTS AS EVIDENCED BY THEIR PRODUCTION OF MYRIASIS IN STANDARD LABORATORY ANIMALS.

United States Patent 3,631,047 SUBSTITUTED 3,3-DIPHENYLPIPERAZINES AND 3,3-DIPHENYLPIPERAZIN-2-ONES Meier E. Freed and Scott J. Childress, Philadelphia, Pa., assignors to American Home Products Corporation, New York, N.Y. No Drawing. Filed Dec. 23, 1968, Ser. No. 786,367

Int. Cl. C07d 51/72 US. Cl. 260-268 R 7 Claims ABSTRACT OF THE DISCLOSURE The disclosure is directed to substituted 3,3-diphenylpiperazines, substituted 3,3-diphenylpiperazin-Z-ones and relates compounds. The compounds are useful as sympat-homirnetic agents as evidenced by their production of mydriasis in standard laboratory animals.

This invention relates to a new class of piperazine compounds and to a method for their preparation. More pari N R alkylatlon Llkgm ticularly, it relates to substituted 3,3-diphenylpiperazines and substituted 3,3-diphenylpiperazin-Z-ones. The compounds of this invention may be represented by the formula:

R ca 2 alkyl, hydrogen, lower alkanoyl, benzoyl and lower alkoxycarbonyl,

B is selected from the class consisting of 0x0 [0] and hydrogen )2] with the proviso that when B is oxo, A is not hydrogen, lower alkanoyl, benzoyl and lower alkoxycarbonyl; and

R and R are the same or difierent members selected from the class consisting of hydrogen, halogen, lower alkyl and lower alkoxy.

As used herein the terms lower alkyl, lower alkoxy and the like describe groups containing from one to about five carbon atoms, provided that lower alkyl groups contain from two to about four carbon atoms when they are part of the pyrrolidino (lower) alkyl, piperidino (lower) alkyl and morpholino (lower) alkyl groups.-

Typical examples of the compounds of this invention are I-(Z-phenethyl)-3,3-diphenylpiperazine and 1-(3-dimethylaminopropyl) -3 ,3-diphenyl-Z-piperazinone.

The new and useful compounds of this invention may be prepared by the process which is hereinafter schematically illustrated:

N R N R reduction 31ml...

-(III) (IV) 1 ll: 1 u d t reduction Where A, R and R are as defined above, and R is lower alkyl or aryl.

Many of the starting compounds utilized in the preparation of the compounds of the present invention are known compounds which are readily available from commercial are known compounds which are readily available from commercial sources, while others can be easily prepared in accordance with standard organic procedures Wellknown to those skilled in the art.

Because the nitrogen containing compounds of the present invention are basic, advantage may be taken of the water solubility of salts of these compounds formed with acids in the isolation and/or purification of the above compounds for oral or parenteral administration. Of course, only salts formed with pharmacologically-acceptable acids should be employed in therapeutic applications. Particularly eifective salts are those formed with pharmacologically-acceptable acids having a pH value of 3 or lower. Such acids are well-known in the art, for example: hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, phosphoric, acetic, lactic, citric, tartaric, maleic, gluconic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic, acids and the like. These salts may be prepared by procedures commonly employed in the art, for example, reacting the compound with an equivalent weight of the selected acid in aqueous solution and concentration of the solution. Other known procedures may also be employed.

The preparation of the 1-substituted-3,S-diphenylpiperazine (IV) is carried out in two steps by one of three alternate routes as shown above. In one route 3,3- diphenylpiperazin-2-one (II) is reacted with a reducing agent, such as lithium aluminum hydride, diborane or the like to form 2,2-diphenylpiperazine (III). The reaction may be carried out in an organic solvent medium such as ether, dioxane, tetrahydrofuran at a temperature range of about to 100 C. for about 6 to 72 hours. Preferably the reaction is carried out at a temperature range of about 30 to 70 C. for about 12 to 36 hours.

The compound (III) may then be alkylated with an appropriate alkylating agent such as an alkyl halide or an epoxide to add the desired alkyl substituent and results in the 1 substituted-3,3-diphenylpiperazine (IV). The reaction is preferably carried out in an organic solvent medium at a temperature range of about to 135 C. for a period of about 1 to 18 hours. Preferably the reaction is carried out at a temperature range of about 45 to 100 C. for a period of about 6 to 12 hours. When the reaction is complete the products may be recovered and separated by well-known techniques. For instance, the reaction mixture may be filtered and the filter cake washed with tetrahydrofuran, and then with methanol.

The filtrates may be combined and concentrated under vacuum. The residue may be redissolved in ether and dried over magnesium sulfate, filtered and concentrated to obtain the product.

Alternately, the compound (III) is then acylated with an appropriate acylating agent, such as an acyl halide or haloformate, to produce the acylated 3,3-diphenylpipera- Zine (V). The latter compound (V) may then be reduced with an appropriate reducing agent such as lithium aluminum hydride, to form the l substituted-3,3-diphenylpiperazine (IV) product of the present invention. The reaction is preferably carried out in an organic solvent medium at a temperature range of about 0 to 100 C. for a period of about 6 to 72 hours. Preferably the reaction is carried out at temperature range of about to 70 C. for a period of about 12 to 36 hours.

When the reaction is complete the products may be recovered and separated by well-known techniques.

Another route for the formation of 1-substituted-3.3- diphenylpiperazine (IV) consists of alkylating a 3.3-diphenylpiperazin-Z-one with a halogen derivative of the substituent desired to be added in the 1-position in a suspension of sodium hydride or the like in an organic solvent medium, such as dimethylformamide or the like to form the 1-substituted-3,3-diphenylpiperazinone (VI). The reaction is preferably carried out at a temperature range of about 0 to 100 C. for a period of about 1 to 24 hours. Preferably the reaction is carried out at a temperature range of about 30 to 75 C. for a period of about 6 to 12 hours. The latter is then reduced with an appropriate reducing agent such as lithium aluminum hydride as described above, to form the 1-substituted-3,3- diphenylpiperazine (IV) product of the present invention. When the reaction is complete the products may be recovered and separated by well-known technioues.

The 1-substituted-3,3-diphenylpiperazine (IV) and 1- substituted-3,3-diphenyl-2-piperazinone (VI) of the present invention have utility in experimental pharmacology. The compounds are sympathomimetric agents which is particularly evidenced by their production of mydriasis in a host.

In the pharmacological evaluation of the compounds as mydriatic agents the in vivo effects are tested as follows. The compound to be tested is administered intraperitoneally to three mice (14 to 24 grains) at each of the following doses: 400, 127, 40 and 12.7 milligrams per kilogram of host body weight (mg/kg). The animals are watched for a minimum of two hours during which time signs of general stimulation (that is, increased spontaneous motor activity, hyperactivity on tactile stimulation, twitching), general depression (that is, decreased spontaneous motor activity, decreased respiration) and autonomic activity (that is miosis, mydriasis, diarrhea) are noted.

The compounds of the present invention in the above test procedure were shown to be mydriatic agents at dosages of 4, 12.7, 127 and 400 milligrams per kilogram of the body weight of the host (mg/kg).

When the compounds of this invention are employed as described above, they may be administered alone or in combination with pharmacologically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmacological practice. For example, they may be administered orally in the form of tablets or capsules containing such excipients as starch, milk, sugar, certain types of clay and so forth. They may be administered sublingually in the form of troches or lozenges in which the active ingredient is mixed with sugar and corn syrups, and then dehydrated sufiiciently to make it suitable for pressing into a solid form. They may be administered orally in the form of solutions which may contain coloring and flavoring agents or they may be injected parenterally, that is intramuscularly, intravenously or subcutaneously. For parenteral administration they may be used in the form of a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic.

The dosage of the present therapeutic agents will vary with the form of administration and the particular compound chosen. Furthermore, it will vary with the particular subject under treatment. Generally, treatment is initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. It will generally be found that when the composition is administered orally. larger quantities of the active agent will be required to produce the same effect as a smaller quantity given parenterally. In general, the compounds of this invention are most desirably administered at a concentration level that will generally afford effective results without causing any harmful or deleterious side effects.

In order more clearly to disclose the nature of the present invention, specific examples of the practice of the invention are hereinafter given. It should be understood. however, that this is done solely by way of example and is intended neither to delineate the scope of the invention nor limit the ambit of the appended claims.

In the examples the following abbreviations are used which are well-known in the art: for phenyl and O for phenoxy. Other abbreviations used are also wellknown: g. for grams, ml. for milliliter, mole for gram molecular weight, etc.

EXAMPLE 1 .The following example illustrates the preparation of 2,2-diphenylpiperazine dihydrochloride, a compound of Formula III.

The reaction may be illustrated:

To a stirred suspension of lithium aluminum hydride (84.4 grams, 2.22 mole) in dry tetrahydrofuran (2 liters), in a 5 liter 3-necked atlask fitted with a seal-type stirrer, dropping funnel and condenser fitted with a calcium chloride filled drying tube, was added, in portions, 3,3-diphenylpiperazine-Z-one (140 grams, 0.555 mole). The reaction was heated at reflux for 3 hours, stirred overnight at room temperature, and then refluxed again for 6 hours and cooled in an ice-bath. The reaction mixture was decomposed by the cautious addition of water (255 milliliters) and stirred 3 hours at room temperature. The inorganic material was filtered off and the filter-cake washed with tetrahydrofuran, then with methanol. Combined filtrates were concentrated under reduced pressure. The residue was taken up in anhydrous ether (1500 ml.), filtered clear and again concentrated. Residue solidified after standing several days. The yield was 121.9 grams equal to 92.1% of theoretical yield. Treatment of an ether solution of 2,2-diphenylpiperazine with dry hydrogen chloride gave a white hydrochloride which was filtered off, washed with ether, dried and recrystallized from 292-294 C.

Based on the formula C H N Cl it was calculated that the elemental analysis by weight would be 61.72 percent carbon, 6.47 percent hydrogen, 8.99 percent nitrogen and 22.78 percent chlorine. The product was analysed and the content was found to be 61.71 percent carbon, 6.26 percent hydrogen, 9.05 percent nitrogen, and 22.70 percent chlorine. The foregoing may be expressed:

Analysis.Calculated for C H N Cl (percent): C, 61.72; H, 6.47; N, 8.99; Cl, 22.78. Found (percent): C, 61.71; H, 6.26; N, 9.05; Cl, 22.70.

In the pharmacological evaluation described above, the product was found to be a mydriatic agent at 4 mg./kg. administered orally. The highest non-lethal dose administered was 127 mg./kg.

EXAMPLES 2-27 Following the procedure of Example 1 but substituting appropriate reactants for 3,3-diphenylpiperazin-2-one, the following substituents of R and R are added when B is (H) and R is hydrogen:

Example CH O C aO

EXAMPLE 28 The following example illustrates the preparation of 1-ethoxycarbonyl-3,3-diphenylpiperazine, a compound of Formula V and 1-methyl-3,3-diphenylpiperazine, hydrochloride, a compound of Formula IV.

The reaction may be illustrated:

A solution of 2,2-dipenylpiperazine (15.7 grams, 0.0242 mole), triethylamine, 5.4 grams, 0.0532 mole) and ether ml.) was cooled to 3 C. A solution of ethyl chloroformate (5.78 grams, 0.0532 mole) in ether (50 ml.) was added at 39 C. over a period of hour. The mixture was stirred in the ice-bath for 1 hour, then at room temperature for 5 hours. The solid was filtered off to give 4.34 grams of trimethylamine hydrochloride. The filtrate (was concentrated under vacuum. The residue was dissolved in ether (200 ml.) and treated with saturated ethanolic hydrogen chloride to pH 1. The hydrochloride of the product, l-ethoxycarbonyl 3,3 diphenylpiperazine, separated as an oil from the ether. On standing this oil solidified. It was filtered off, washed with ether, and dried. The yield was 6.65 grams having a melting point of 228- 231 0., being equivalent to a 79.3 percent yield.

The hydrochloride was converted back to base by suspending it in 75 ml. water and adding 50 percent aqueous sodium hydroxide to raise the pH to 12. A solid formed which was extracted into ether, washed with saline, dried over magnesium sulfate and filtered clear. This filtrate was concentrated under vacuum. The residue (4.6 grams) was dissolved in dry tetrahydrofuran (75 ml.) and added to a stirred suspension of lithium aluminum hydride (0.86 gram, 0.0225 mole) in 50 ml. of tetrahydrofuran, refluxed 28 hours and cooled. Water (4 ml.) was added slowly, stirred several hours, and filtered. The filter-cake was washed first with tetrahydrofuran and then with methanol. The filtrates were combined and concentrated under reduced pressure. The residue was redissolved in ether (250 ml.) and dried over magnesium sulfate, filtered and again concentrated. The residue, a yellow oil (4.9 grams) was dissolved in 30 ml. ethanol.

The clear solution was treated with ethanolic hydrogen chloride (pH=l) and diluted to 500 ml. with ether. After standing in the cold (5 C.) a solid formed and was filtered off, washed and dried. The product was recrystallized from methanol-acetone and afforded 2.4 grams (56.8 percent of theoretical yield) of white crystals of 1-methy1- 3,3-diphenylpiperazine monohydrochloride, having a melting point of 244-245 C.

Analysis-Calculated for C H ClN (percent): C, 70.70; H, 732; C1, 12.27; N, 9.70. Found (percent): C, 70.64; H, 7.23; CI, 11.98; N, 9.47.

In the pharmacological evaluation described above, the product was found to be a mydriatic agent at 12.7 mg./ kg. administered orally. The highest non-lethal dose administered was 127 mg./kg.

EXAMPLE 28A The following illustrates the preparation of l-acetyl-3,3- diphenylpiperazine, a compound of Formula IV.

To a solution of 2,2-diphenylpiperazine (5.7 g., 0.0242 mole) and triethylamine (2.70 g., 0.0266 mole) in ether (200 ml.) at 10 C. is added, slowly and with stirring and cooling, a solution of acetyl chloride (1.95 g., 0.025 mole) in 50 ml. of ether. Following addition, the reaction mixture is stirred for 1 hour. The solid material (triethylamine hydrochloride) is filtered off and Well washed with ether. The solvent is removed from the combined filtrate and washings under reduced pressure, leaving a solid residue of product.

EXAMPLE 28B The following illustrates the preparation of 1-ethyl-3,3- diphenylpiperazine, a compound of Formula IV.

To a stirred suspension of lithium aluminum hydride (3.8 g., 0.1 mole) in 250 ml. of dry tetrahydrofuran is added slowly a solution of 1-acetyl-3,3-diphenylpiperazine (9.5 g., 0.025 mole) in 150 ml. of tetrahydrofuran. After the addition is completed the reaction mixture is stirred and refluxed 8 hours. After cooling, water (14 ml.) is added slowly and with stirring and cooling. After complete addition the reaction mixture is allowed to stir at room temperature for 2 hours, then filtered. The filter cake is washed well with tetrahydrofuran, then with isopropanol. Solvent is removed from the combined filtrate under reduced pressure. The residue is taken up in ether and treated with dry hydrogen chloride. The precipitated hydrochloride is then filtered oif, washed with ether and recrystallized.

EXAMPLE 28C The following illustrates the preparation of (2-methylpropionyl)-3,3-diphenylpiperazine, a compound of Formula IV.

In the manner of example 28A, :1 solution of 2,2-diphenylpiperazine (5.7 g., 0.0242 mole) and triethylamine (2.7 g., 0.0266) in ether is treated with an ethereal solution of (2-methyl)propionyl chloride to give the desired product.

EXAMPLE 28D The following illustrates the preparation of 1-(2- methylpropyl)-3,3-diphenylpiperazine, a compound of Formula IV.

In the manner of example 28B, a solution of 1-(2- methylpropionyl)-3,3-diphenylpiperazine (6.2 g., 0.02 mole) in dry tetrahydrofuran (150 ml.) is added to a stirred suspension of lithium aluminum hydride in 250 ml. of tetrahydrofuran. Following work-up the product is isolated as the hydrochloride.

EXAMPLES 29-5 4 Following the procedures of Example 28A and Example 28B but substituting appropriate compounds for 2,2- diphenylpiperazine, acetyl chloride, and 1-acetyl-3,3-diphenylpiperazine, the following substituents of R R and A may be added where B is (H) 8 EXAMPLE 5s The following example illustrates the preparation of l-(2-phenethyl-3,3 diphenylpiperazine, a compound of Formula IV.

The reaction may be illustrated:

Gil 20112131 II *7 EL3N t Q a t EXAMPLE 56 Following the procedure used in Example 55, 2,2-diphenylpiperazine is mixed with cinnamyl bromide and heated in an inert solvent for 20-24 hours to obtain 1-cinnamyl-3,3-diphenylpiperazine.

EXAMPLE 5 7 Following the procedure used in Example 55, 2,2-diphenylpiperazine is mixed with an equivalent amount of morpholinoethyl chloride and heated in an inert solvent for 20-24 hours to obtain 1-(morpholinoethyl)-3,3-diphenylpiperazine.

EXAMPLE 58 The following example illustrates the preparation of 3,3-diphenyl-l-piperazineethanol, a compound of Formula IV.

To a stirred mixture of 2,2-diphenylpiperazine (5.0 g., 0.021 mole), powdered potassium carbonate (4.15 g., 0.03 mole) and benzene (60 ml.) at 45 C., was added a solution of 2-bromoethanol (2.63 g., 0.021 mole) in M4 hour. The mixture was stirred at reflux for 3% hours after the addition had been completed, then it was cooled and filtered. The filtrate was freed of solvent to give the crude product.

A sample of the product was converted to the fumarate by adding 3.888 g. (0.01376 mole) in acetone (50 ml.) to a solution of 0.793 g. (0.00688 mole) fumaric acid in acetone ml.). The salt that separated on cooling was recrystallized twice from methanol-acetone to give the fumarate, 2.13 g. melting at l72-175 C.

Analysis for C H N O .Calculated percent: C, 70.56; H, 7.11; N, 8.23. Found (percent): C, 70.29; H, 7.24; N, 7.96.

EXAMPLE 59 Following the procedure used in Example 58, 3-bromopropanol is substituted for 2-bromoethanol to obtain 3,3- diphenyl-l-piperazinepropanol.

EXAMPLES 60-71 Following the procedure used in Example 55 but substltutmg appropriate compounds for 2,2-diphenylpiperazine, and phenethylbromide the following substituents for R R and A may be added when B is hydrogen:

The following example illustrates the preparation of 1-phenoxyethyl-3,3-diphenylpiperazine, a compound of Formula IV.

The reaction may be illustrated:

A mixture of 2,2-diphenylpiperazine (5.0 grams, 0.021 mole), fl-bromophenetole (4.23 grams, 0.021 mole), triethylamine (2.13 grams, 0.021 mole) and toluene (75 ml.) was stirred at reflux for 24 hours. The mixture was cooled and the triethylamine hydrobromide (3.37 grams, having a melting point of 245-248 C.) was filtered off. The filtrate was concentrated. The residue was recrystallized from aqueous ethanol to give 3.65 grams of product, 1-phenoxyethy1-3,3-diphenylpiperazine (a 48.5 percent of theoretical yield), having a melting point of 9597.5 C.

Analysis.Ca1culated for C H N O (percent): C, 80.41; H, 7.31; N, 7.82. Found (percent): C, 80.55; H, 7.05; N, 7.67.

In the pharmacological evaluation described above, the product was found to be a mydriatic agent at 12.7 mg./ kg. administered parenterally. The highest dose administered was 400 mg./kg. and was non-lethal.

EXAMPLES 78-86 Following the procedure of Example 77 but substituting appropriate compounds for 2,2-diphenylpiperazine and fl-bromophenetole the following substituents for R R and A may be added when B is hydrogen:

Example R R A 78- 02115 H OCH2CHCH 79- C3H7 H OOHCHZ CH 2)s 2 OH; 4 0 OHzOH (OH CHg) (3H3) CHZCHZ C211 OCH2CH2OH H 4 O 011(011 CH H 93 2 H 0 CH2CH (CHQCHQ) 10 EXAMPLE 87 The following example illustrates the preparation of 1-(3-dimethylaminopropyl) 3,3 diphenylpiperazine, a

compound of Formula IV.

The reaction may be illustrated:

E (CHa)2NCH CH CH Cl toluene A mixture of 2,2-diphenylpiperazine (2.5 grams, 0.0105 mole), 3 dimethylaminopropylchloride hydrochloride (1.66 grams, 0.0105 mole), and triethylamine (2.34 grams, 0.0231 mole) and dimethylformamide (20 ml.) was stirred at 70 C. for 4% hours. The mixture was poured into ice water (75 ml.). It was extracted with ether (175 ml. in 3 portions). The combined extracts were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated to give a residual oil (2.5 grams).

The fumarate was prepared by adding 2.324 grams (0.00719 mole) of the base in acetone (50 ml.) to a hot solution of fumaric acid (1.252 grams, 0.01078 mole) in acetone (150 ml.). The solid that was obtained on cooling was filtered oif, washed and dried to give 2.59 grams of solid 1-(3 dimethylaminopropyl)-3,3-diphenylpiperazine, a 53.4 percent of theoretical yield, having a melting point of 165.5168.5 C.

Analysis.-Calculated for C H N O (percent): C, 65.17; H, 7.09; N, 8.45. Found (percent): C, 64.69; H, 6.99; N, 8.44.

In the pharmacological evaluation described above, the product was found to be a mydriatic agent at 400 mg./ kg. administered orally.

EXAMPLE 88 The following example illustrates the preparation of 1- (3-dimethylaminopropyl) 3,3 diphenylpiperazine, a compound of Formula IV. (See Example 93.)

The reaction may be illustrated:

I Q N Q i tetrahydrofuran Q r H H To a suspension of lithium aluminum hydride (3.8 grams, 0.1 mole) in dry tetrahydrofuran ml.) is added, slowly, and with stirring, a solution of 1-(3-dimethylaminopropyl)-3,3-diphenyl 2 piperazinone (8.4 grams, 0.025 mole) in dry tetrahydrofuran. After addition is complete the reaction is stirred and refluxed 18 hours, then cooled. The reaction mixture is decomposed by the slow addition of Water (12-14 ml), followed by stirring for two hours. The inorganic material is filtered from the solution and washed with tetrahydrofuran and isopropyl alcohol. The solvent is removed by evaporation at reduced pressure, and the residue is then taken into ether, filtered clear, and treated carefully with dry hydrogen chloride. The product, 1-(3-dimethylaminopropyl)-3,3-diphenylpiperazine hydrochloride is purified by recrystallization from pentane-acetone.

1 1 EXAMPLE 89 The following example illustrates the preparation of l- (3-dimethylaminopropyl) 3,3 diphenylpiperazine, a compound of Formula IV.

A mixture of 2,2diphenylpiperazine (5.0 grams, 0.021 mole), 3-dimethylaminopropylchloride hydrochloride (3.32 grams, 0.021 mole), triethylamine (4.26 grams, 0.042 mole) and toluene (75 ml.) was stirred at reflux for 26 /2 hours. The mixture was cooled, then filtered to remove the triethylamine hydrochloride formed. The filtrate was concentrated to dryness. The residue was dissolved in ether and filtered with the aid of Super-Cel. Addition of anhydrous hydrogen chloride followed by filtration gave 7.48 g. hydrochloride. Recrystallization from methanol-acetone gave 1.68 grams unreacted 2,2- diphenylpiperazine hydrochloride. The mother liquor was concentrated and the residue was recrystallized from isopropanol to give the product hydrochloride, 2.44 grams decomposing at about 130 C. This was converted to the base by treating its aqueous solution with potassium carbonate to pH and extracting three times with ether. The ethereal extracts were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and freed of solvent to give the product as an oil, 1.4 grams.

The base was converted to the fumarate by adding 1.240 grams (0.00383 mole) in acetone ml.) to a boiling solution of fumaric acid (0.668 gram, 0.00575 mole) in acetone (100 ml.). The solution was concentrated to a volume of 100 ml. The solid which precipitated on chilling was recrystallized from methanol-acetone to give the fumarate, 1.40 grams, melting at 165166.5 C.

Analysis.-Calculated for C H N O (percent): C, 65.17; H, 7.09; N, 8.45. Found (percent): C, 64.69; H, 6.99; N, 8.44.

EXAMPLE 90 The following example illustrates the preparation of 1- allyl-3,3-diphenylpiperazine, a compound of Formula IV.

A mixture of 2,2-diphenylpiperazine (5.0 grams, 0.021 mole), allyl bromide (2.55 grams, 0.021 mole), triethylamine (2.13 grams, 0.021 mole) and toluene (75 ml.) was stirred at reflux for 28% hours. The mixture was then cooled and filtered to remove the triethylamine hydrobromide formed. The filtrate was freed of solvent to give 8.3 grams oil.

The base was converted to the fumarate by adding a solution of 6.19 grams to a boiling solution of fumaric acid (2.58 grams) in acetone (300 ml.). The resulting solution was freed of solvent and the residue recrystallized twice from ethyl acetate to give the fumarate, 5.00 grams, melting at 174175 C.

Analysis.Calculated for C H N O (percent): C, 70.03; H, 6.64; N, 7.10. Found (percent): C, 70.04; H, 6.41; N, 6.99.

In the pharmacological evaluation described above, the product was found to be a mydriatic agent at 127 mg/kg. administered orally. The highest dose administered was 400 mg./kg. and was non-lethal.

EXAMPLE 91 The following example illustrates the preparation of ladamantoyl-3,3-diphenylpiperazine, a compound of Formula IV.

To a solution of 2,2-diphenylpiperazine (5.00 grams, 0.021 mole) and a triethylamine (2.13 grams, 0.021 mole) in acetone (20 ml.) was added a solution of l-adamantanecarboxylic acid chloride (4.18 grams, 0.021 mole) in acetone (30 ml.) over a period of /3 hour. The mixture was stirred at reflux for 4 hours, then cooled. The solid was filtered off, washed and dried. Recrystallization from acetonitrile gave the product, 4.99 grams (59.3% yield) melting at 182l84 C.

12 AnaIysis.-Calculated for C H N O (percent): C, 80.96; H, 8.05; N, 6.99. Found (percent): C, 81.20; H, 8.18; N, 7.12.

EXAMPLE 92 The following example illustrates the preparation of a,3,3-triphenyl-l-piperazineethanol, a compound of Formula IV.

A solution of 2,2-diphenylpiperazine (5.0 grams, 0.021 mole) in benzene (20 ml.) was heated to 60 C. A solution of styrene oxide (2.53 grams, 0.021 mole) in benzene was added at 60 C. over a period of /4 hour. The solution was stirred at reflux for 3 hours, then cooled and freed of solvent. The residue was recrystallized from etherpentane to give the product, 2.88 grams (38.3 percent yield) melting at -121 C.

Analysis.Calculated for C H N O (percent): C, 80.41; H, 7.31; N, 7.82. Found (percent): C, 80.16; H, 7.42; N, 7.73.

EXAMPLE 93 The following example illustrates the preparation of 1-(3-dimethylaminopropyl)-3,3-diphenyl-Z-piperazinone, a compound of Formula VI.

The reaction may be illustrated:

II CH3 1 O /NV (IJIIZCHZCI-IZN l t@ N NaHDMI Y/ Ill mm: 11 IIZCHZCI T l H To a suspension of sodium hydride (0.88 gram, 0.02 mole of a 55 percent by weight dispersion in mineral oil) and dimethylformamide (10 ml.) was added a solution of 3,3-diphenyl-Z-piperazinone (5.05 grams, 0.02 mole) in dimethyl formamide (45 ml.) over a period of A, hour. The mixture was stirred at room temperature for 1% hours after completion of the addition. A solution of freshly distilled 3-dirnethylaminopropylchloride (2.44 grams, 0.02 mole) in dimethylformamide (20 ml.) was added over a period of A1 hour. The mixture was stirred at room temperature for 23 hours, then poured into water ml.). The mixture was acidified to pH 1 with concentrated hydrochloric acid. After extraction with petroleum ether (3 portions, 50 ml. each), it was basified to pH 12 with 50 percent aqueous sodium hydroxide. The resulting mixture was extracted with ether (3 portions, 100 ml. each). The combined extracts were dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in boiling acetonecyclohexane (300 ml.). The solution was concentrated to half volume. The solid that was formed on chilling was recovered to give 1.84 grams unreacted 3,3-diphenyl-2-piperazinone. The mother liquor was concentrated to a volume of 10 ml. The solid that was formed on chilling was filtered off and recrystallized twice from cyclohexane to give 1.12 grams of product 1-(3-dimethylaminopropyl)-3,3-diphenyl-2-piperazinone, having a melting point of 788l C., (a 16.6 percent of theoretical yield).

Analysis.-Calculated for C H N O (percent): C, 74.74; H, 8.07; N, 12.45. Found (percent): C, 74.97; H, 8.07; N, 12.32.

In the pharmacological evaluation described above, the product was found to be a mydriatic agent at 400 mg./kg. administered orally.

EXAMPLES 94-105 Following the procedure of Example 93 but substitutmg appropriate starting materials for 3,3-diphenyl-2-piper- 13 azinone and 3-dimethylaminopropylchloride, the following substituents of R R and A may be obtained when B is oxo. As used below C H N is pyrrolidino, C H N is piperidino and C H NO is morpholino.

EXAMPLE 106 The following example illustrates the preparation of 1-methyl-3,3-diphenyI-Z-piperazinone, a compound of Formula VI.

To a suspension of sodium hydride (0.88 gram, 0.02 mole of a 55 percent dispersion in mineral oil) and dimethyl formamide (10 ml.) was added a solution of 3,3- diphenylpiperazine-2-one (5.05 grams, 0.02 mole) over a period of /2 hour. The mixture was stirred at 50 C. for 1 hour, then cooled to 30 C. A solution of methyliodide (2.84 grams, 0.02 mole) in dimethylformamide (10 ml.) was added in 10 minutes. The mixture was stirred at 50 C. for 24 hours. It was cooled, then poured into water (200 ml.) and acidified to pH 1 with concentrated hydrochloric acid. It was extracted three times with light petroleum ether. The aqueous phase was basified to pH 12 with 50 percent sodium hydroxide and then extracted three times with ether. The combined etheral extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous sulfate and freed of solvent. The residue was recrystallized twice from acetonecyclohexane and once from benZene-pentane to give the product, 1.55 grams (29.1 percent yield) melting at ISO-153 C.

Analysis.-Calculated for C17H13N2O (percent): C, 76.66; H, 6.81; N, 10.52. Found (percent): C, 76.44; H, 6.74; N, 10.72.

In the pharmacological evaluation described above, the product was found to be a mydriatic agent at 127 mg./ kg. administered orally. The highest dose administered was 400 mg./ kg. and was non-lethal.

1 4 What is claimed is: 1. The compounds having the formula A ,l R. L R2 N K? H where A is selected from the class consisting of lower alkyl, phenyl, halophenyl, trifiuoromethylphenyl, lower alkylphenyl, lower alkoxyphenyl, phenoxy(lower)alkyl, halophenoxy (lower alkyl, trilluoromethylphenoxy (lower) alkyl, lower alkylphenoxy(lower)alkyl, lower alkoxyphenoxy(lower)alkyl, omega-amino(lower)alkyl, omega(lower alkylamino lower) alkyl, omega-di (lower) alkylamino- (1o'wer)alkyl, pyrro1idino(lower)alkyl, piperidino(lower) alkyl, morpholino(lower)alky1, hydrogen, lower alkanoyl, benzoyl and lower alkoxycarbonyl; and R and R are the same or different members selected from the class consisting of hydrogen, halogen, lower alkyl and lower alkoxy.

2. A compound as defined in claim 1 which is: 2,2-diphenylpiperazine dihydrochloride.

3. A compound as defined in claim 1 which is: l-methyl- 3,3-diphenylpiperazine hydrochloride.

4. A compound as defined in claim 1 which is: 1-(2- phenethyl -3 ,3-diph enylpiperazine.

5. A compound as defined in claim 1 which is: l-phenoxyethyl-3,3-diphenylpiperazine.

6. A compound as defined in claim 1 which is: 1-(3-dimethylaminopropyl -3 ,3-diphenylpiperazine.

7. A compound as defined in claim 1 which is: l-allyl- 3,3-diphenylpiperazine.

References Cited UNITED STATES PATENTS 2,400,022 5/1946 Pollard 260-268 R 2,633,467 3/1953 de Bonneville 260-268 MK 2,649,450 8/1953 Strong et al. 260-268 MK 3,171,837 3/1965 Freed 260-268 MK 3,390,139 6/1968 de Benneville 260-268 MK OTHER REFERENCES DONALD G. DAUS, Primary Examiner U.S. Cl. X.R.

260-2472, 247.5, 268C, 268PH, 268MK, 268H, 268PC;

Em Column 2, in the reaction sequence going from Formula III to mg UNITED STATES PATENT OFFHCE CERTEFWA @FF @QREQTWN Patent No 3 3 7 Dated Decemba-I' 97 Inventofls) Meier E0 Freed and Scott JO Childrees It is certified that? error appears in the above identified patent and that said Letters Patent are hefireby corrected as shown below:

Formula V the characterization should read M aeylation rather than "alkylation" as follows:

ac lation mg? UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3, 3 Dated December 28, 1971 manure Meier E. 'Freed and Scott J. Childress 2 It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

691mm lines 7- the characterization of the reaction should read Et N rather than "E" as follows:

H I v CH CH CH N CH I 2 2 2 3 2 N NCH CH CH 01 O N (CH3)? 2 2 2 C l I H Et N H toluene Column 6, line 20, "2,2 51ipeny1piperazine should read 2,2-diphenylpiperazine Signed and sealed this 19th day of September 1972.

(SEAL) Attest:

EDWARD M.PLETCHER,JR. ROBERT GOTTSCHALK Attesting Officer Commissioner of Patents 

